Ovarian cancer is the most deadly gynecologic malignancy in the United States principally due to its usual diagnosis at an advanced stage and eventual development of drug resistance. A dismal 5-year overall survival rate of 30% has remained largely unchanged over the past two decades despite intensive research efforts. RNA interference (RNAi) is a mechanism of gene regulation that can be manipulated through the use of short interfering RNA (siRNA) to specifically suppress genes that contribute to chemotherapy resistance. The Bcl-2 family of anti-apoptotic proteins have been implicated in the development of drug resistance in ovarian cancer and represent promising targets for siRNA mediated inhibition. However, a major hurdle for clinical implementation of siRNA is effective tumor-specific intracellular delivery. This application will test in vivo a modular delivery system consisting of antibodies directed against Her2/neu and mesothelin to promote receptor-mediated intracellular siRNA uptake by ovarian cancer cells and a pH-responsive polymer to enhance endosomal escape of siRNA into the cytoplasm. The project aims are to: 1) demonstrate and optimize Her2/neu and mesothelin mediated siRNA delivery in vivo; 2) evaluate siRNA directed against Bcl-2 family members for cytotoxic potentiation of carboplatin 3) test the combined efficacy of proapoptotic siRNA and carboplatin to augment survival in a mouse xenograft model of intraperitoneal ovarian cancer. This research builds upon previous highly promising work by the applicant, Maria Corinna Palanca-Wessels M.D., Ph.D, and comprises part of a career development plan that will enable her to successfully transition into a fully independent research position. Her long-term goal is to establish a translational research program to test novel cancer therapies that exploit tumor specific antigens and RNA interference for more effective treatment of malignancies. Her mentor, Dr. Oliver W. Press, M.D., Ph.D., and a carefully selected K08 advisory committee are respected leaders in the relevant fields of immunotherapy, polymer technology, intracellular siRNA delivery and ovarian cancer. Dr. Press is a world-renowned physician scientist with an established track record of guiding junior faculty to productive independent careers in cancer research. He is an outstanding mentor and will provide her with abundant resources and assistance to achieve her career objectives. Drs. Press and Palanca-Wessels have prepared a career development plan that will integrate didactic coursework in the fields of RNA biology, drug development, and biostatistics with practical acquisition of laboratory skills at the benchside. Regular progress meetings with Dr. Press and her K08 advisory committee will serve an important role in guiding her toward new research directions in anticipation of applying for independent funding and achieving her long-term goal of becoming an expert in the fields of antibody and RNAi-based therapeutics for ovarian cancer treatment. Additionally, she will utilize the outstanding resources offered by both the Fred Hutchinson Cancer Research Center and the University of Washington to foster her career development.